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Formyl acetamide azole derivative and use thereof

A technology of azole derivatives and formylacetamide, applied in the field of drug synthesis, can solve the problems of low recurrence rate, high drug resistance and metabolic toxicity, and difficult to overcome.

Active Publication Date: 2020-04-03
LIAOCHENG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, although CYP51 inhibitors have the advantages of high efficiency and low recurrence rate, they also have the disadvantages of easy drug resistance and high metabolic toxicity.
In particular, the problem of drug resistance that they have all emerged, once it occurs, it is extremely difficult to overcome

Method used

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  • Formyl acetamide azole derivative and use thereof
  • Formyl acetamide azole derivative and use thereof
  • Formyl acetamide azole derivative and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Example 1 2-((1H-imidazol-1-yl)methyl)-N-(1-(2-chloropyrimidin-4-yl)piperidin-4-yl)-3-oxo-3-benzene Preparation of propionamide

[0054] Step 1 Preparation of (1-(2-chloropyrimidin-4-yl) piperidin-4-yl) tert-butyl carbamate

[0055] Dissolve 2,4-dichloropyrimidine (1.0eq) in DMF solution, add K 2 CO 3 (1.5eq), under stirring, N-(piperidin 4-yl) tert-butyl carbamate (1.2eq) was added, and reacted at room temperature for 6 hours. After the reaction was complete, ice water was added, and a solid was precipitated, which was filtered and dried to obtain the obtained compound is required.

[0056] Step 2 Preparation of 1-(2-chloropyrimidin-4-yl)piperidin-4-amine

[0057] Dissolve tert-butyl (1-(2-chloropyrimidin-4-yl)piperidin-4-yl)carbamate (1.0eq) in dichloromethane solution, add excess trifluoroacetic acid (10.0 eq), adding saturated K 2 CO 3 The solution was adjusted to alkali, extracted with dichloromethane, and the organic layer was collected Na 2 SO 4 , dry ov...

Embodiment 2

[0065] Example 2 2-((1H-1,2,4-triazol-1-yl)methyl)-N-(1-(2-chloropyrimidin-4-yl)piperidin-4-yl)-3 - Oxo-3-phenylpropanamide;

[0066] Yield: 72.3%; mp: 145.9–148.2℃. 1 H NMR (400MHz, DMCO-d 6 )δ8.77(s,1H),8.39–7.93(m,2H),7.84(dd,J=40.6,9.2Hz,1H),7.67(ddt,J=16.5,13.6,3.1Hz,1H),7.56 –7.28(m,1H),6.70(s,1H),6.16(d,J=15.0Hz,1H),5.23(dd,J=24.7,8.6Hz,1H),4.92–4.73(m,1H), 4.37(dd,J=24.7,8.6Hz,1H),3.83(p,J=15.2Hz,1H),3.53–3.00(m,2H),2.12–1.86(m,1H),1.74(ddt,J= 24.8,15.2,11.0Hz,1H). 13 C NMR (101MHz, DMSO-d 6 )δ196.32,168.60,163.89,156.72,156.18,151.75,144.06,137.04,132.74,129.14,128.61,97.18,54.13,52.79,48.55,47.50,30.70.ESI-MS m / z:44 + ;462.2[M+Na] + ;4387.2[M-H] - .

Embodiment 3

[0067] Example 3 2-(((1H-imidazol-1-yl)methyl)-N-(1-(2-chloropyrimidin-4-yl)piperidin-4-yl)-4-methyl-3- Oxyvaleramide;

[0068] Yield: 68.7%; mp: 143.3–146.7℃. 1 H NMR (400MHz, DMCO-d 6)δ7.92(s,1H),7.80(d,J=15.0Hz,1H),7.18(d,J=15.0Hz,1H),6.78(dd,J=15.0,0.6Hz,1H),6.35( s,1H),6.16(d,J=15.0Hz,1H),4.39(dd,J=23.3,12.8Hz,1H),4.26(dd,J=14.6,11.0Hz,1H),4.14(dd,J =23.2,12.7Hz,1H),3.72(p,J=15.2Hz,1H),3.49–3.13(m,4H),2.69–2.33(m,1H),2.04–1.80(m,2H),1.65( ddt,J=24.8,15.2,11.0Hz,2H),1.04(d,J=12.8Hz,6H). 13 C NMR (101MHz, DMSO-d 6 )δ212.74,167.16,163.89,156.72,156.18,139.84,128.74,120.63,97.18,61.33,49.12,48.55,47.50,38.24,30.70,18.56.ESI-MS m / z:405.2[M+H] + ;427.2[M+Na] + ;403.2[M-H] - .

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Abstract

The invention belongs to the field of drug synthesis, and relates to a novel formyl acetamide azole derivative and pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, preparation methods, and a drug composition containing the compound. The formyl acetamide azole derivative disclosed by the invention has a relatively strong antifungal effect. A formyl acetamide azole compound asshown in a general formula I provided by the invention is shown in the specification.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and particularly relates to new formylacetamide azole derivatives and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, their preparation methods and their application in antifungal drugs. Background technique [0002] Fungal infection (fungal infection, IFI) mainly includes superficial fungal infection and deep fungal infection. Among them, deep fungal infection not only invades the skin and subcutaneous tissue, but also affects internal tissues and organs, making it clinically characterized by high mortality and difficult cure. In addition, with the widespread abuse of broad-spectrum antimicrobials, immunosuppressants, and chemoradiotherapy drugs in clinical practice, drug resistance of pathogenic fungi is becoming more and more frequent. However, there is still no effective treatment so far. Once fungal drug resistance occurs, complex dosing regimens are often required, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D233/60C07D249/08A61K31/506A61K31/4164A61K31/4196A61P31/10
CPCC07D401/14C07D233/60C07D249/08A61P31/10Y02A50/30
Inventor 孙彬董岳安云飞
Owner LIAOCHENG UNIV
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